How to diagnose hypogonadism?

The diagnosis of hypogonadism (also known as testosterone deficiency or low testosterone) requires the presence of characteristic symptoms/signs combined with low testosterone levels.1-7 Symptoms of hypogonadism resemble those of aging; as a consequence, hypogonadism is often overlooked. To prevent this, clinical guidelines have developed diagnostic procedures to confirm hypogonadism in a patient who has symptoms and/or signs of testosterone deficiency, which are summarized below.1-7 These include symptomatic evaluation, medical history, physical examination and measurement of testosterone levels.

    Symptomatic evaluation

    Evaluation of symptoms that may be related to low testosterone is mandatory for making the diagnosis of hypogonadism. Use of validated symptom questionnaires, such as the Aging Males’ Symptoms (AMS) questionnaire is helpful in daily clinical practice for symptomatic evaluation. The AMS can be used both as part of the diagnosis, and for monitoring of symptomatic improvement during testosterone therapy.

    The most common and reliable symptoms of hypogonadism are sexual symptoms.8 These include reduced or absent libido, erectile dysfunction, difficulty achieving orgasm, reduced intensity of orgasm, and reduced sexual sensation in the genital region. Common non-sexual symptoms include fatigue, lack of energy, decreased vitality, inability to perform vigorous activity, depressed mood, irritability, “brain fog” (memory problems, a lack of mental clarity, inability to focus), and decreased motivation. These symptoms may occur singly or in any combination. Decreased libido is one of the primary symptoms of hypogonadism. It may occur, with or without any of other symptoms or signs, and is strongly suggestive of hypogonadism in men >50 years without obvious other causes, such as relationship issues and stress. Increased probability of low sexual desire, poor morning erections, erectile dysfunction and reduced physical vigor is seen with testosterone levels below 13 nmol/L (370 ng/dL),8 however, these symptoms can also occur in men with higher testosterone levels.

    Medical history

    Chronic diseases, such as type 2 diabetes and heart disease, are associated with low testosterone. Furthermore, certain medications, especially opioids,9-12 selective serotonin reuptake inhibitors (SSRIs),13 statins,14-16 and glucocorticoid medications 17,18 reduce testosterone levels. Therefore, comorbid conditions must be comprehensively investigated in every patient. Acute illnesses are associated with the development of functional hypogonadism; in patients with acute illness, measurement of testosterone levels should be postponed.

    Physical examination

    Because obesity is frequently associated with hypogonadism, measuring body weight and height in order to find out BMI, along with measurement of waist circumference, should be done in all men. Small testicles can also be an indication of a reduced androgen status.

    Measurement of testosterone levels

    Measurement of total testosterone is mandatory for making the diagnosis of hypogonadism.1-7 Because testosterone levels display a circadian rhythm with highest levels in the morning and lowest in the afternoon,19 it is commonly recommended that total testosterone levels are measured before 11 a.m. However, as explained in “Practical advice for diagnosing hypogonadism”, this is not an absolute requirement.

    1.

    Symptomatic men with a total testosterone < 12.1 nmol/L (350 ng/dL) are eligible for testosterone therapy (provided they have no contraindications.1,2,4-6,20,21

    2.

    For symptomatic men with borderline low or low-normal testosterone levels, assessment of free testosterone levels is recommended. This can be done by measuring SHBG levels and using a free testosterone calculator, or by measuring free testosterone directly using equilibrium dialysis.

    3.

    Proposed diagnostic thresholds for free testosterone by calculation or equilibrium dialysis range from 65 - 100 pg/mL (225 - 347 pmol/L).1,2

    4.

    Symptomatic men with increased LH levels but normal testosterone levels should be considered as having hypogonadism.4 Increased LH level indicates Leydig cell insufficiency and merits consideration of testosterone therapy even if testosterone levels are in the low-normal range.

    5.

    A trial of testosterone therapy in symptomatic men with testosterone levels above 12.1 nmol/L (350 ng/dL) can be considered.2,4,6,7,21

    While most guidelines recommend a second testosterone blood test to confirm the first low testosterone value, the clinical value of this has been questioned by prominent clinicians and scientists who have decades of hands-on experience in diagnosing and treating men with hypogonadism.22 A notable study showed excellent correlation (r = 0.849) between the testosterone level at first blood draw and the mean of 7 blood draws taken subsequently over 1 year.23 It concluded that in middle-aged and elderly men, a single testosterone measurement reflects fairly reliably the annual mean testosterone level.23 Measuring testosterone levels twice within a short period of time imposes additional burden on patients and clinicians. Therefore, a single value showing low testosterone in symptomatic men is usually enough to make the diagnosis of hypogonadism.22

    Clinical guidelines are increasingly acknowledging the value of assessing free testosterone when making the diagnosis of hypogonadism, especially in symptomatic men who have borderline low or low-normal total testosterone levels, or conditions that are known to affect SHBG levels, summarized in table 1.1,2,4 Multiple studies have shown that free testosterone levels may correlate more closely to symptoms/signs of hypogonadism, especially sexual dysfunction, than total testosterone levels.24-29 This underscores the potential clinical utility of assessing free testosterone levels in the evaluation of testosterone deficiency.

    Free testosterone levels are determined by SHBG levels; the higher the SHBG level the lower the free testosterone level. In men attending a men's health center, there can be a remarkably wide distribution of SHBG levels (range 6-109 nmol/L) – and consequently free testosterone levels - in both younger and older men, with a nearly 20-fold difference from the lowest to the highest values.30 In younger men ≤54 years old, mean SHBG was 28 nmol/L (range 6-88 nmol/L), while in older men ≥55 years old, mean SHBG was 37 nmol/ L (range 11-109 nmol/L).30

    Because direct measurement of free testosterone with equilibrium dialysis is expensive, clinical guidelines recommend calculating free testosterone using an online free testosterone calculator.

    Elevated SHBG --> Reduced free testosterone Reduced SHBG --> Elevated free testosterone

    Drugs: anticonvulsant, estrogens, thyroid hormone

    Drugs: GH, glucocorticoids, testosterone, anabolic androgenic steroids

    Hyperthyroidism

    Hypothyroidism

    Hepatic disease

    Obesity

    Aging

    Acromegaly

    Smoking

    Cushing Disease

    AIDS/HIV

    Insulin resistance (metabolic syndrome or type 2 diabetes)

     

    Non-alcoholic fatty liver disease (NAFLD)
    Nephrotic syndrome

     

    Table 1: Conditions associated with elevated or reduced SHBG levels.1